Preparing for a clinical trial of interventions to maintain normal vaginal microbiota for preventing adverse reproductive health outcomes in Africa

人体表面覆盖着一种叫做人类微生物区系的细菌。据信，这个微生物群落包含的细胞数量至少是人体的10倍，基因数量是人体的100倍。近年来，在表征人类微生物区系方面取得了相当大的进展。研究人员发现，这些微生物群落是人体正常运作所必需的，例如，消化肠道中的复杂碳水化合物和防止病原体入侵。与此同时，正常微生物区系的失衡已被证明与许多疾病有关。人类阴道还含有主要由乳酸菌组成的细菌群落，这些细菌被认为可以保护女性和她们的胎儿免受病原体的入侵。当这些细菌群落失衡时，病原体可能进入子宫、胎盘、胎儿周围的膜或腹腔，导致盆腔炎、流产、早产或母婴败血症。这些不平衡还与艾滋病毒和其他性传播感染在性伴侣和母子之间的传播增加有关。一些失衡在过去被诊断为细菌性阴道病(BV)(使用患者报告的症状和阴道液的显微镜检查)。不幸的是，BV一直是出了名的难以治疗，即使治疗成功，复发率也很高。由于研究人员未能防止BV在怀孕期间复发，他们也未能防止随后不良的妊娠结局。在这项发展赠款中，我们将开发干预措施，以维持最初治愈BV后的正常阴道微生物群。这项研究的参与者将是卢旺达妇女，她们是艾滋病毒和其他性传播疾病的高危人群，但没有怀孕。我们将要求一组15名妇女每周使用两次阴道凝胶(0.75%甲硝唑凝胶)，为期两个月，第二组15名妇女，每周三次使用名为Gynoflor的阴道益生菌片剂，为期两个月，第三组15名妇女，每周三次使用名为生态女性的阴道益生菌胶囊，为期两个月。这两种益生菌都含有被称为乳杆菌的“健康”细菌，而Gyneflor也含有非常低剂量的雌三醇。另一组15名女性将组成对照组。所有群体中的所有妇女都将接受更安全的性行为和计划生育咨询，以及关于如何将研究干预措施纳入她们通常的阴道卫生实践的个性化咨询。在项目结束时，我们将评估我们是否能够在2个月的干预期间以及停止干预后的4个月内保持健康的阴道微生物区系。我们还将评估这些干预措施的可接受性和可行性。这项试验的一个新方面是，我们不仅将使用标准方法来评估阴道微生物区系(即报告症状和阴道液显微镜)，还将使用基于细菌基因测序的新分子方法。这使得能够全面和深入地描述微生物群落。这项试验的结果将被用来计划最有希望的干预措施的更大规模的随机对照临床试验(S)。

Human body surfaces are covered by bacteria called the human microbiota. This microbial community is believed to contain at least 10 times the number of cells and 100 times the number of genes in the human body. Considerable progress has been made in characterising the human microbiota in recent years. Researchers have discovered that these microbial communities are needed for proper functioning of the human body, for example to digest complex carbohydrates in the gut and to prevent pathogen invasion. At the same time, imbalances of the normal microbiota have been shown to be associated with a number of diseases. The human vagina also contains bacterial communities of mostly lactobacilli that are thought to protect women and their foetuses from pathogen invasion. When these bacterial communities are imbalanced, pathogens may enter the uterus, placenta, membranes surrounding the foetus, or abdominal cavity, causing pelvic inflammatory disease, miscarriages, pre-term births, or maternal or neonatal sepsis. These imbalances have also been associated with increased transmission of HIV and other sexually transmitted infections (STIs) between sexual partners and mother-child pairs. Some of the imbalances have been diagnosed in the past (using symptoms reported by the patient and microscopy of vaginal fluid) as bacterial vaginosis (BV). Unfortunately, BV has been notoriously difficult to treat, and even when treated successfully, recurrence rates are high. Because researchers have not been able to prevent BV recurrences during pregnancy, they have also not been able to prevent subsequent poor pregnancy outcomes.In this development grant, we will develop interventions to maintain normal vaginal microbiota after initially having cured BV. The study participants will be Rwandan women who are at high risk of HIV and other STIs but who are not pregnant. We will ask one group of 15 women to use a vaginal gel (0.75% metronidazole gel) twice per week for 2 months, a second group of 15 women to use a vaginal probiotic tablet called Gynoflor thrice weekly for 2 months, and a third group of 15 women to use a vaginal probiotic capsule called Ecologic Femi thrice weekly for 2 months. Both probiotics contain 'healthy' bacteria called lactobacilli, and Gyneflor also contains a very low dose of oestriol. A further group of 15 women will form the control group. All women in all groups will receive safer sex and family planning counselling as well as individualised counselling on how to integrate the study interventions into their usual vaginal hygiene practices. At the end of the project, we will evaluate whether we were able to maintain healthy vaginal microbiota during the 2-month intervention period as well as the 4 months after cessation of the interventions. We will also evaluate the acceptability and feasibility of these interventions.A novel aspect of this trial is that we will not only use standard methods to evaluate the vaginal microbiota (i.e. reporting of symptoms and microscopy of vaginal fluid) but also new molecular methods based on the sequencing of bacterial genes. This allows for a holistic and in-depth characterisation of microbial communities.The results of this trial will be used to plan a larger randomized controlled clinical trial of the most promising intervention(s).